The method to manufacture a molding by compacting molding material represented by powder granule, etc., has widely been used in various industrial fields for example not only in the field of medicines and foods (functional foods and general foods), but also in the field of electronic material such as semiconductor sealing resin molding, molding of battery related products, molding of powder metallurgy related products, and molding of electronic functional parts as well as in the field of agricultural chemicals and sanitary products.
In the field of medicines, especially in case of medicines for oral administration, a solid molding called “tablet” is one of the most widely used form of medicines, because of their various merits, e.g., they are simple to manufacture and easy to take. Among them, a molding having core therein is called compression-coated tablet because it is each manufactured by distributing and compacting the powder granule as an outer layer around the core (center tablet).
Since the compression-coated tablet having a core therein can separate medicines that undergo change of formulation into the core and the outer layer, an improved stability is expected due to low probability of contact between medicines. Besides the compression-coated tablet present an effective way to mask bitter taste of core and improve appearance of tablet, as well as to protect against damaging environmental factors (such as light or humidity). They can also be used as release controlled medicines that include an outer layer having a rapid releasability and a core in the form of an enteric tablet or a sustained release tablet.
Up until now, when manufacturing a molding with core such as a compression-coated tablet, the core was made as a molded piece in advance in a separate tableting machine, then it was moved to a die of a different compression-coated tablet machine where the powder granule forming the outer layer was fed and then compressed. For this reason, compared to the typical method for manufacturing compression moldings, this method presents some serious problems such as more steps and low productivity.
Besides, in this conventional method feeding cores as molded pieces, since the molded pieces as cores are to be fed one by one in the die of a rotary table which revolves at a high speed, sometimes a core may not be fed and sometimes they may be fed in excess and therefore problems such as manufacturing of products without core or products with plural cores occur easily. For this reason, in order to preserve quality, there appear a necessity for complicated mechanisms and systems for surveillance of the feeding of core and inspection of the final molding. Thus the machines engaged in the process of manufacturing of a molding with core become larger in size and more complicated.
Besides, in the traditional method of feeding the core, it was important that the core was horizontally disposed in the middle of the outer layer powder granule within the die and then compression-molded. For this reason some moldings disorders occur very easily. For example when the core is not in the middle, the outer layer becomes thinner in that region; also the capping occurs because of decline in the moldability. Another disorder is a lamination when cracks on the surface of the molding appear in layers.
In order to prevent offset in the centering of the core due to the centrifugal force of the rotary table, Japanese Patent Laid-open Pub. No. Sho55-48653 discloses an inspection method of the centering of the core by visual inspection after it is fed; Japanese Patent Laid-open Pub. No. Sho61-60298 discloses a system provided with a multi-optical-axis identification sensor in conjunction with core feeder to automatically correct the core position; and Japanese patent Laid-open Pub. No. Hei9-206358 discloses a method for preventing the offset in the core centering by use of a system for automatically correcting the core feeding positions on the basis of information acquired from a CCD imaging device.
However, even when the above core centering systems are used, problems of precision of the centering and stability of feeding of cores still remain unsolved and therefore step of the high-speed rotary table as in the ordinary tableting machines (40 to 60 rpm) is difficult, so the actual operating ability is limited to approx. 30 rpm and the productivity is low.
In regard to the size of a molding with core, in the conventional method, due to dispersions in the core centering and to insufficient adhesion strength between the core and the outer layer which may arise from utterly separate molding of the core and the outer layer, the outer layer minimum thickness of 1 to 1.5 mm is required, and inevitably, a molding with core becomes at least 2 to 3 mm larger than the core itself. Therefore compared to coreless a molding, the molding with core has the tendency to become larger, which is an obstacle in the efforts to miniaturize the molding.
As far as the shape of core is concerned, in the traditional method in which cores are externally fed, it is necessary to provide a dedicated feeder, conforming to the shape of the core. Therefore, when manufacturing a molding with diversely shaped cores, a diversity of core feeder is needed and the problem of lacking in versatility still remains left.
In the traditional method, since a core prepared beforehand is fed, it is necessary for the cores to have moldability that will allow an harmless delivery through a supply line into the die, as well as shape that will allow smooth passage. Therefore there are some limitations in the shape and properties of the core. For example, the traditional method does not provide a way to manufacture a molding having a core that is not the solid or a core that is the very powder granule.
As far as the shape of the punch in the prior art is concerned, different types of punches are used, depending on the shape of the molding to be compressed. In some instances, punches with specific shape are used. For example, in case of a troche-shaped molding, used in medical field, in which the central part is cut out, it is very difficult to fill in evenly the powder granule, using an ordinary punch. Also, to open the central part, a so-called ring-punch, or a double punches is used for the compression molding.
When manufacturing extremely small and complex in a shape molding used in diverse applications including electronic parts, due to the complexity in the shape, there is a difference in the compression ratio of the powder granule. Because of this difference, the molded products may have largely different powder granule densities, depending on the sites, with the result that the molding is easily broken or damaged. Thus, in order to solve these problems, a method has been executed in which powder granule is filled in such that the powder granule densities of the molding are the same by separately moving the bottom center punch and the lower outer punch, of multiple punches having the same structure as the ring punch which is seen in the lower punch structure of the rotary powder compression molding machine disclosed in Japanese Patent Laid-open Pub. No. Sho52-126577.
However, the conventional so-called ring punch, i.e., punch having a multiple-structure is used as an additional aid for filling the powder granule and to secure ring-shaped cavities and that is why it is utilized mainly as lower punch. Even the center punch is used in stationary mode.
The manufacturing methods and apparatus for molding having a single core are subjected to the above situations and problems. However, in regard to a molding having plural cores, since in the state of the art any rotary tableting machines that can manufacture such a molding does not exist, there are no prior art of practical use.
In terms of references, Japanese Patent Pub. No. Hei2-243158 describes a method for reducing the size of a compression-coated tablet by introducing plural small-sized core pellets into a single die. However, in addition to involving the above situations and problems of the molding with single core, there are some new problems due to increase in the manufacturing process steps. For example, there also increases the frequency of manufacturing of a molding without core or with more than one core as set forth above. In other instances, due to interference among cores in the die, the positions of different cores are not consistent, but are different for each molding.
Following is a reference to the prior art related to a molding. As described above, the method to manufacture compression-coated tablets consisted of feeding cores, prepared in advance in a different tableting machine, into a die, feeding the outer layer around the core and then applying compression. For this reason, the core was restricted by some physical factors, mainly the moldability (friability and hardness) for allowing the supply into the die. Therefore due to problems of handling and poor feeding ability of the core caused by wearing away of cores, only cores with high moldability were used in this method.
In order to change the formulation to improve moldability of the core, a conventional method has been employed, namely to reduce the amount of molding material with poor moldability, or on the contrary to increase the amount of molding material with high moldability. In other words, since the active medicine ingredients (effective ingredients or main ingredients) commonly possess poor moldability, there were only two alternatives either to reduce the amount of effective ingredients of the core, or to improve wear resistance by feeding large amount of excipients etc., to increase the weight of the core.
In case of the traditional compression-coated tablet, since more or less, offset in positioning of the fed core occurs, it was difficult to reduce the thickness of the outer layer, which was one of the reasons for the rather large size of a compression-coated tablet.
Similar problems with the moldability also exist in the field of the so-called conventional tablet, manufactured by compressing mixture of effective ingredients and excipients, etc. Since in most cases effective ingredients are actually ingredients with poor moldability, under the existing circumstances the methods to improve the moldability are, just like in the above described case with the compression-coated tablet, only two either to decrease the ratio of addition of the effective ingredients in the formulation, or to increase the ratio of addition of excipients, etc., for the improvement of the moldability, ignoring the fact that this will enlarge the size of the tablet.
Sill, there is another method to improve the moldability of some ingredients with poor moldability by granulation, etc. However, considering the influence of the granulation solvent over the stability and the increase in costs due to increase in the number of the manufacturing process steps and also considering the fact that even after granulation the moldability of some ingredients do not improve, this method cannot be used as means for fundamentally modifying the moldability of all ingredients. Much more essential is the improvement achieved through modifying the composition of ingredients and diminishing the concentration of effective ingredients.
Therefore, at present there are only two methods to improve the moldability of molding containing ingredients with poor moldability either to decrease the ratio of ingredients with poor moldability which occupy in the formulation, or to feed large amount of ingredients that improve the moldability and thus increase total weight of products.
However, especially in pharmaceutics, the dosage of effective ingredients is strictly fixed and therefore, in case that the effective ingredients have poor moldability, the only two options are either to decrease the amount of those effective ingredients per tablet and to increase the number of tablets to be taken, or, without increasing the number of tablets to be taken, just to enlarge the size of the tablets. This often caused problems with swallowing, especially among older people and infants.
Next follows description of prior art for manufacture of a molding that contain granular molding material, which are highly brittle and lacking moldability, such as microcapsules and various coated granule, used in pharmaceutics and food industry. However, description herein on such granular molding material will be limited to microcapsules.
In microcapsules, the granulated ingredients are protected from external influences and therefore it can be expected that their stability will increase and any possibility for undesired reaction with other ingredients in the same mixture will be eliminated. The solidification of liquid active drug or low-melting-point active drug can be made to a tablet, and they can also prevent oxidation reactions as well as photolytic reactions, and combination alterations thereof and thus increase the stability of the active drug compounds. Furthermore, they can also control the reactions of the active drug in a living body. For example, when solution, made by dissolving of insoluble active drug into solvent, is enclosed in capsules, its absorption efficiency in the living body is improved. Or, by capsulation of one of the ingredients, susceptible to chemical reactions, it is isolated and allowed to enter chemical reactions only after being used. Furthermore, liquid products are inconvenient to be utilized, therefore they are made into apparently solid particle or powder and thus by improving their weight and handling properties make them suitable for feeding into confectionery, cosmetics and agricultural chemicals. In other words, the area of application of granulated molding material is indeed very wide.
The term “microcapsules” broadly includes besides the microcapsules themselves, also seamless capsules, mini soft capsules, micro spheres (micro beads) etc. The range of their utilization in pharmaceutics depends on their size, shape and characteristics. They can be used as multiple-kinds of active drugs that are consumed at once, such as multivitamins. Since there are special microcapsules such as sustained release microcapsules and enteric-coated microcapsules, they can also be fed to active drugs as controlled release preparations.
Up to now, when intended for oral administration, in most cases those microcapsules were manufactured as capsule preparations, filled into hard capsules, due to their easy handling properties. This made them very expensive as well as difficult to take. Not only this, but gelatin capsules, that enclosed microcapsules, were easy to be tempered and often were infected with foreign bodies, which could cause unfortunate accidents. For this reason many efforts were put to develop a method that would allow avoiding the use of gelatin capsules and enable turning the microcapsules into tablets.
Thus, turning the microcapsules into tablets has some advantages especially in the fields of pharmaceutics and food industry. However the manufacturing method for tablets, containing microcapsules, which was based on the prior art, presented two major problems. The first one is the decline in hardness and wear-resistant properties of tablets, due to lack of moldability in microcapsules themselves. The second one is the increase in variation of the microcapsules' content in tablets, due to separation or segregation of microcapsules and excipients during tabletting process.
Tablets containing microcapsules is disclosed in Japanese Patent Laid-open Pub. Nos. Sho50-36619, Sho53-142520, Hei2-72113, Hei2-237914, Hei9-52847 and 2000-16932. In general, however, microcapsules are coreless structures made of encapsulated in gelatin lipid-soluble or water-soluble ingredients as active drug. For this reason, when high physical pressure is applied from outside, the coating gets broken and the active drug ingredients are released.
Next, the coating of the microcapsules is made of gelatin which is an ingredient with poor moldability, and hence, when compared with excipients, used in pharmaceutics and food industry, the microcapsules are extremely poor in moldability. Such poor moldability is attributable to the poor plastic deformability of the microcapsules themselves. On the contrary, this characteristic makes it possible to maintain the shape of capsules even inside tablets.
Furthermore, shape of other capsules, such as seamless capsules and micro-spheres, is smooth surfaced perfect sphere and, combined with the fact that the ingredient of the coating is gelatin, which has poor moldability at tabletting, it makes manufacturing of tablets as single units impossible.
Thus, when microcapsules, that completely lack moldability, are molded together with excipients, in order to improve this lack of moldability, it is necessary to apply high tabletting pressure during tabletting process. However, the tabletting with a high pressure might lead to new problems, such as breaking of the microcapsule coating. So at present the manufacturing process is stuck in a situation in which increasing pressure in order to improve moldability will cause breaking of the microcapsule coating, and on the other hand decreasing pressure in order to prevent destruction of the coating will result in insufficient moldability.
In order to secure the moldability and prevent the destruction of the coating due to increased compression stress upon tabletting, the microcapsules are sandwiched between layers, formed by granulated excipients and a layer of excipients is used as a buffer-agent against compression during the tabletting process. This technique is disclosed in Japanese Patent laid-open Pub. No. Sho50-36619. In Japanese Patent Laid-open Pub. No. Sho53-142520 there is disclosed a description that lactose, ordinary crystalline cellulose and starch in large amounts can be used as excipients. Crystalline cellulose is described herein to be especially effective as excipients. Furthermore, in Japanese Patent Laid-open Pub. No. Sho61-221115 is disclosed a method, employing about 10 to 50% ordinary crystalline cellulose.
However, when manufacturing such tablets, there are two options either to decrease the microcapsules content by amount, i.e., the amount of the active drug contained therein, or to feed large amount of excipients in order to keep a predetermined amount of active drug or microcapsules containing the predetermined amount of the active drug. In other words, it is practically impossible to manufacture tablets with high content of microcapsules. In case of medicines for example, the amount of the active drug that must be contained in one tablet or one dosage depends on the efficacy of this active drug and therefore the amount of the active drug cannot be reduced. As a result, the amount of the excipients is increased and the tablets become intolerably large in size.
There is also a different method to achieve moldability by granulating microcapsules with a binder and/or suitable excipients. Japanese Patent Laid-open Pub. No. Hei9-52847 discloses a tablet manufacturing method by wet mixing granulation. Another tablet manufacturing method using similar techniques for wet mixing granulation is disclosed in Japanese Patent Laid-open Pub. No. 2000-16932. However, tablets that contain 28% microcapsules of this embodiment had 1% friability (in accordance with Japanese Pharmacopoeia) and not very good moldability. Furthermore, the mixing granulation method, in which the granule is formed by high-speed rotation of blades and kneading, involves some problems such as destruction of the microcapsules during granulation steps. Besides, gelatin, which is the main material for microcapsules, swells at contact with water and so it would be difficult in terms of steps and qualities to use water as the granulation solvent. Therefore ethanol or other organic solvents should be used as granulation solvent, which leads to new problems such as increase of the production costs and residual solvent in the manufacturing environment and in the product itself.
Thus, it is very difficult to manufacture tablets that contain large amount of microcapsules, using the traditional methods. The problem is not only the moldability of the tablets, but also the dispersion of microcapsule content in the tablet, caused by the dissociation or segregation of the microcapsules and the excipients during the process of tablet forming.
In general, granulated bodies, containing large particles like microcapsules and small particles like excipients, differ in friction coefficient, depending on the size of the particles and the state of their surface. For this reason, due to movement and vibration of the rotary table during the process of tablet formation, the granulated bodies are often separated into large particles and small particles. Thus the granulated bodies are divided into a group of large size particles and a group of small size particles (particle size segregation). Furthermore, since the microcapsules and the excipients also differ in density, it is easy to cause segregation due to density difference (density segregation).
Due to these two segregation factors, as the time for tablet formation elapses, the product also undergoes separation or segregation. As a result, the separated or segregated tablet material is fed and molded in a die, so the amount of microcapsules in the tablets undergoes a change. There are two methods to prevent the separation or segregation described above. The first one is to granulate the microcapsules and the excipients and make them one particle. The second one is to decrease the content of microcapsules and feed the tablet material into a die before the separation or segregation occurs. However, the first granulation method presents some problems such as problems of the above-described solvent and increase in the cost, as well as insufficient moldability. The second method also cannot provide a substantial solution to all problems, as it just reduces the separation or segregation, but in doing so it makes impossible to prescribe large amounts of microcapsules.
In case of the traditional molding, containing microcapsules, the microcapsules more or less come to the surface of the molding and problems such as desorption of the microcapsules from the molding cannot be avoided. Problems such as poor moldability and friability also remain unsolved.
Main reference numerals in diagrams are as follows: 1: rotary table, 3: die, 4A, 83B: upper central punch, 4B, 83A: upper outer punch, 5A: lower central punch, 5B: lower outer punch, 21, 22: granular residue removal unit, 30, 31, 32, 33: reduction device, 35: rail of lower central punch, 36: rail of lower outer punch, 37: bottom of central punch, 41, 42, 43: descent cam of upper central punch, 44,46: upper temporary compression roller, 45, 47: bottom temporary compression roller, 48: preliminary compression roller for upper central punch, 49: preliminary compression roller for lower central punch, 50: main compression roller for upper central punch, 51: main compression roller for lower central punch, 52: rail of upper central punch, 53, 54, 55: descent cam for upper outer punch, 56: rail of upper outer punch, 57 (57A, 57B): granular residue, 62, 63: ascent cam, 65, 66: force rail, 67: preliminary compression roller for upper outer punch, 68: preliminary compression roller for lower outer punch, 69: main compression roller for upper outer punch, 70: main compression roller for lower outer punch, 73: control roller for vertical sliding motion of lower outer punch, 74: control roller for vertical sliding motion of upper outer punch, 78, 80: compression bed for outer punch, 79,81: compression bed for central punch, 82: control roller for vertical sliding motion of central punch, NP: core, OP1: first outer layer, OP2: second outer layer.